The present invention relates to manufacturing processes for the preparation of a pharmaceutical dosage form comprising nifedipine and candesartan cilexetil and optionally at least one diuretic characterized in that nifedipine is released in the body in a controlled (modified) manner and the candesartan cilexetil is released rapidly (immediate release (IR)) and optionally the diuretic is released rapidly (immediate release (IR)) and the pharmaceutical dosage forms obtainable by these processes.
The calcium antagonist nifedipine is, as established active ingredient, successfully used in hypertension therapy and known from e.g. GB 1173862.
The angiotensin II antagonist candesartan, its prodrug candesartan cilexetil and its medicinal use as antihypertensive drug is known from EP 0 459 136.
Diuretics are medicaments used for eliminating water from the human or animal body. In some instances, elimination of salts, too, is increased. This results in a reduction of plasma volume and peripheral resistance. Diuretics are primarily employed for lowering blood pressure. There are various types of diuretics. Carboanhydrase inhibitors (acetazolamide): blockade of proton secretion and sodium bicarbonate re-absorption, mainly at the proximal tubulus. Nowadays use limited almost exclusively to ophthalmology for the treatment of glaucomas. Loop diuretics (furosemide, torasemide, bumetanide, etacrynic acid, piretanide): reversible inhibition of an Na/2Cl/K carrier system at the thick ascending limb of the loop of Henle. Potassium-sparing diuretics (amiloride, triamterene): blockade of the Na channels at the late distal tubulus and at the collecting tube, inhibition of Na re-absorption, as a consequence reduced K secretion. Aldosterone antagonists (spironolactone, potassium canrenoate, eplerenone): competitive binding at the aldosterone receptor, as a consequence inhibition of Na re-absorption and K secretion, used for ascites associated with cirrhosis of the liver and as additional therapeutic for chronic heart failure. Thiazide diuretics and other sulphonamide diuretics (hydrochlorothiazide (=HCTZ), chlorothiazide, chlorthalidone, xipamide, indapamide, mefruside): reversible inhibition of the Na—Cl cotransport at the early distal tubulus (luminal), inhibition of carboanhydrase, reduction of GFR, hydrochlorothiazide frequently employed in combination with antihypertensive agents. The addition of a diuretic such as, for example, HCTZ in monotherapy enhances the hypotensive action of the combination.
Combinations of a diuretic and angiotensin II antagonists are known to the person skilled in the art, for example from EP 1 306 088 B (candesartan and furosemide), but also the following fixed-dose combinations for treating high blood pressure such as, for example, Hyzaar® (=losartan potassium plus HCTZ) from Merck, Co-Diovan® (=valsartan plus HCTZ) from Novartis or Boehringer's Micardis Plus® (=telmisartan plus HCTZ).
In view of the biological properties of nifedipine and/or nisoldipine and the angiotensin II antagonists, it is crucial for both active ingredients to be absorbed from the low sections of the bowel without significant loss of bioavailability. This is the case with only about 30-50% of all active ingredients, and therefore appropriate selection of the combination active ingredients is crucially important for developing an IR/slow-release combination product.
It is advantageous especially for the long-term therapy or prophylaxis and secondary prophylaxis of cardiovascular disorders to have the active ingredients available in a form which, through a modified release of active ingredients, leads to a reduction in the peak-trough ratio and makes administration once a day possible.
In the development of formulations, account must also be taken of the physicochemical and biological properties of the active ingredients, for example the relatively low water solubility of nifedipine (approx. 9 mg/l) and the plasma half-life of about 2 hours. Accordingly, special pharmaceutical formulations with which nifedipine undergoes a modified release, taking account of its physicochemical and biological properties, are necessary for the desired administration once a day.
In the sense of the present invention the term release in the body in a controlled (modified) manner with respect to nifedipine has the meaning that 85% nifedipine (based on the declared amount of nifedipine) is released from the dosage form over a period of at least 4 and at most 24 hours, and less than 20% of the nifedipine within 4 hours, and from 43 to 80%, more preferably from 45 to 75%, in particular preferably from 50 to 70% of the nifedipine within 12 hours in an in-vitro release test carried out according to the USP release method using apparatus 2 (paddle) at 100 revolutions per minute in 900 mL of phosphate buffer pH 6.8 with addition of 1% sodium lauryl sulphate as the release medium at 37° C.
In the sense of the present invention the term release in the body is rapid (immediate release (IR)) with respect to candesartan cilexetil and/or a diuretic has the meaning that that at least 70%, preferably at least 80% of the candesartan cilexetil (based on the declared amount of the candesartan cilexetil) is dissolved within a period of 60 minutes in an in-vitro dissolution test carried out according to the USP dissolution method using apparatus 2 (paddle) at 75 revolutions per minute in 900 mL phosphate buffer pH 6.5 with the addition of 0.7% Tween 20 as the dissolution medium at 37° C.
In the sense of the present invention the term release in the body is rapid (immediate release (IR)) with respect to a diuretic has the meaning that that at least 70%, preferably at least 80% of the HTCZ (based on the declared amount of the HTCZ) is dissolved within a period of 60 minutes in an in-vitro dissolution test carried out according to the USP dissolution method using apparatus 2 (paddle) at 75 revolutions per minute in 900 mL phosphate buffer pH 6.5 with the addition of 0.7% Tween 20 as the dissolution medium at 37° C.
Combinations of an angiotensin II antagonist and, firstly, calcium channel blockers or, secondly, diuretics are known from WO 92/10097. Explicitly described are the combinations of eprosartan and nifedipine and eprosartan and hydrochlorothiazide. Specifically disclosed are fast-release hard gelatine capsules and tablets.
Combinations of candesartan cilexetil and hydrochlorothiazide are disclosed in EP 0 753 301B.
Dosage forms releasing the active compounds nifedipine or nisoldipine in combination with an angiotensin II antagonist in modified/delayed form and their preparation are described, for example, in WO 2007/003330. In these formulations, both nifedipine and the angiotensin II antagonist are released in delayed form.
WO2008/044862 discloses pharmaceutical dosage forms comprising an active ingredient combination of at least one calcium channel blocker and at least one angiotensin II antagonist characterized in that the calcium channel blocker is released after a certain lag time immediately whereas the angiotensin II antagonist is released immediately (chronotherapy). Explicitly disclosed are the combinations of losartan and amlodipine.
WO2010/060564 discloses pharmaceutical dosage forms comprising an active ingredient combination of nifedipine or nisoldipine and at least one angiotensin II antagonist and/or at least one diuretic, characterized in that nifedipine or nisoldipine is released in the body in a controlled (modified) manner and the angiotensin II antagonist and/or the diuretic is released rapidly (immediate release (IR)), and also processes for their preparation, to their use as medicaments and to their use for the prophylaxis, secondary prophylaxis or treatment of disorders.
Particularly suitable dosage forms with modified/delayed release of the active ingredient nifedipine are based on osmotic release systems. Preferably, in these osmotic release systems, bi-layer tablets are surrounded by a semipermeable membrane which has at least one orifice. The water-permeable membrane is impermeable for components of the core, but allows water to enter the system from outside by osmosis. The water which has penetrated in then releases, by the resulting osmotic pressure, the active ingredient in dissolved or suspended form from the orifice(s) in the membrane. The overall active ingredient release and the release rate can be controlled substantially via the thickness and porosity of the semipermeable membrane, the composition of the core and the number and size of the orifice(s). Advantages, formulation aspects, use forms and information on production processes are described inter alia in the following publications: U.S. Pat. Nos. 4,327,725, 4,765,989, US 20030161882, EP 1 024 793.
Coated osmotic release systems are likewise known. Thus, EP 0 339 811 describes an osmotic release system consisting of a cellulose acetate coat which comprises nifedipine and swelling agent in the core and is surrounded by a mantle coating of HPMC (hydroxypropylmethylcellulose) having a layer thickness of 0.0025 cm. U.S. Pat. No. 4,948,592, WO 93/03711 and WO 93/00071 describe osmotic release systems comprising a proportion of active ingredient in the core with a delayed release profile and a proportion of the same active ingredient in the mantle coating which can be released directly. Here, the mantle coatings comprise in each case only a small part of the total amount of active ingredient required for pharmaceutical activity. In such case, the pharmacopoeial requirements for content uniformity of dosage forms apply to the total amount of the active ingredient, to the sum of active ingredient in the core and in the mantle coating. Thus, the overall content variability of the active ingredient is somewhere between the typically low variability of tablets prepared by compression and the typically high variability of products prepared by film coating.
When rapid release of a second active ingredient is required, it is necessary to incorporate the entire amount of the second active ingredient into the outer mantle layer of the dosage form. In such cases, i.e. mantle coatings that contain the total amount of an active ingredient (active coatings), the pharmacopoeial requirements for content uniformity of dosage forms solely apply to the amount of the active ingredient in the mantle coating.
It is well known to those skilled in the art that pharmaceutical film coating processes typically result in a higher variability with regard to the mass of the film coating as compared to for example tableting processes with regard to the mass of the tablet cores. This is mainly due to the fact that film coating is a batch process. In a tableting process each single tablet is produced under the same conditions and thus, the variability of the tablet mass is typically low, i.e. relative standard deviations of the tablet mass are typically below 3%, in most cases even below 1.5%. In a pharmaceutical film coating process a complete batch of tablets is coated during a limited time and the film coating mass applied to each single tablets depends on how often and for how long time periods that specific tablets is exposed to the spraying zone. For that reason, the variability of the film coating mass is typically high, i.e. relative standard deviations of the film coating mass are generally above 5% and typically above 7.5% and often even above 15%. As film coatings are often used for cosmetic reasons only (e.g. colour and smooth surface), the high variability is not regarded as critical to the quality. This is also not the case when film coatings are used to protect the tablet from environment effects; in such cases the only requirement is that all tablets are sufficiently protected. In the case of modified release coatings, the film coating mass needs to be controlled in such a way that the variability of the drug release profile is acceptable. This can generally be achieved although the typical high variability of the film coating mass, as the sensitivity of the release profile variability to the film coating variability is less than proportional.
Furthermore, it is well known to those skilled in the art that pharmaceutical film coating processes typically exhibit a certain loss of coating suspension during spraying, i.e. a small but variable and hardly predictable portion of the sprayed coating suspension is deposited on the surface of the coater drum or removed with the exhaust air instead of being deposited on the tablets. In the cases of cosmetic and protective film coatings such losses are typically compensated by predefined overages of e.g. 5-15%. Also in the case of modified release coatings, overages are well established to compensate losses during spraying as the sensitivity of the release profile to the overall film coating mass is less than proportional.
However, in the case of active coatings (and especially if the active ingredient is solely present in the active coating), the inherent variability of the coating process and the poor predictability of spraying losses during manufacturing is in conflict with the pharmacopoeial requirements for content uniformity. Moreover, the pharmacopoeial requirements have become even stricter recently.
Challenges in developing fixed dose combinations using active coating technology are discussed by Desai et al., Pharmaceutical Development Fundamentals: Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms, Pharmaceutical Development and Technology, 1-12 (2012). Chen et al., Modeling of pan coating process: Prediction of tablet content uniformity and determination of critical process parameters, Journal of Pharmaceutical Sciences 99, 3213-24 (2010) provide an overview on factors influencing the coating uniformity. Remarkably, according to these predictions acceptable coating uniformity is only achieved after undesirably long spraying times, such as e.g. up to 1200 min, i.e. 20 hours. Specific examples of active coating applications relating to selected active ingredients, specific coating polymers and specific tablet cores to be coated, are provided in US 2005/0214373 A1, US 2005/0266080 A1, and WO 2012/031124 A2. No general guidance how to optimize process conditions in order to improve active coating processes with regard to content uniformity and determination of coating endpoint are provided therein. Furthermore, coating efficiency is regarded a specific challenge in active coating processes; e.g. Wang et al., An evaluation of process parameters to improve coating efficiency of an active tablet film-coating process, International Journal of Pharmaceutics 427, 163-169 (2012) describe means to optimize coating efficiency.
In the European Pharmacopoeia the requirements for the content uniformity of tablets used to be described in the general chapter 2.9.6 Uniformity of content of single-dose preparations. The acceptance criterion was that out of 10 tablets, all individual assays should be in the range of 85% to 115% of the average assay, or—as stage 2 testing—out of 30 tablets, all individual assays should be in the range of 75% to 125% of the average assay, and not more than 1 tablet should be outside the range of 85% to 115% of the average assay.
However, a new and stricter requirement has been introduced into the European Pharmacopoeia in the Supplement 5.2 as a new general chapter 2.9.40 Uniformity of dosage units. Therein, an acceptance value (AV) is defined as follows:AV=|M−X|+ks wherein X is the mean of the individual contents, M is the reference value, k is the acceptability constant and s is the sample standard deviation. The reference value is depending on the experimental results for X:                if X is between 98.5% and 101.5%, then M=X;        if X is below that range, then M=98.5%;        if X is above that range, then M=101.5%.        
For example, if X is 97.5%, the term |M−X| results in 1%. Similarly, if X is 102.5%, the term |M−X| also results in 1%. For that reason, it is preferred that X is as close to 100% as possible, and it is particularly preferred that X is within the range of 98.5% to 101.5%.
The pharmacopoeial requirement is that AV should not exceed 15%. The test is first performed for n=10 tablets and the AV value is calculated using an acceptability constant of k=2.4. If this test fails, further 20 tablets can be investigated and the AV value for all n=30 tablets is calculated using an acceptability constant of k=2.4. In other words, in order to meet the new strict pharmacopoeial requirements for content uniformity, the mean value of the individual contents should be as close to the range of 98.5%-101.5% as possible. Simultaneously it is also necessary to control the standard deviation of the individual content below 7.5%, preferably significantly below 7.5%.
In addition to the AV requirement it is also required that all individual assays should be in the range of 75% to 125%.
Thus, there is a need to provide manufacturing processes for the dosage form comprising nifedipine and candesartan cilexetil and optionally a diuretic like HTCZ for all scales of pharmaceutical manufacturing that reliably and reproducibly lead to products fulfilling the pharmacopoeial requirements regarding content uniformity of the active ingredient solely present in an active coating. In other words, there is a need to provide active coating processes for all scales of pharmaceutical manufacturing that reliably and reproducibly control the mean of individual contents close to 100% and the respective standard deviation as low as possible, with an inter-tablet variability of the candesartan cilexetil content of less than 5%, preferably less than 4.8%, more preferably less than 4.5%.
It is well known to those skilled in the art, that as a means to improve the uniformity of active ingredient distribution, the active ingredient can be employed in a small particle size. For example, the active ingredient can be used in micronized form. However, in some cases micronization can negatively influence the stability of active ingredients. Without wishing to be limited to any specific theory, this may be due to the increase of reactive surface and/or partial amorphization during micronization, even if such amorphization occurs in a very low and hardly detectable extent.
In US 2007/0082055, it is disclosed that particle size reduction of candesartan cilexetil has an adverse effect on its chemical stability, namely micronization gives rise to the levels of the desethyl compound. In US 2007/0082055, it is further disclosed that the stability of candesartan cilexetil can be improved by a process comprising slurrying a sample of candesartan cilexetil of fine particle size in a suitable solvent for a suitable amount of time and recovering stable candesartan cilexetil of fine particle size.
WO 2008/045006 disclose the stabilization of candesartan cilexetil via the use of antioxidants. WO 2005/070398, WO 2005/084648, WO 2005/079751, and US 2010/0041644 disclose the stabilization of candesartan cilexetil by the use of several compounds, including esters, fatty substances, co-solvents and water-soluble polymers. WO 2005/084648 also mentions the potential use of polyvinyl alcohol.
Thus, there is a need to provide manufacturing processes for the dosage form comprising nifedipine and candesartan cilexetil and optionally a diuretic like HTCZ for all scales of pharmaceutical manufacturing that reliably and reproducibly lead to chemically stable products fulfilling the pharmacopoeial requirements regarding content uniformity of the active ingredient solely present in an active coating.
Terahertz pulsed imaging (TPI) is a recent non-destructive measurement technique that can be used to determine the coating thickness on pharmaceutical tablets. As an imaging technique it can spatially resolve the distribution of the coating layer over the entire surface of a tablet. The technique works by using short pulses of terahertz radiation (FWHM<1 ps), that are focused onto the surface of a tablet. Polymers are semitransparent to terahertz radiation and hence a part of the pulse can penetrate into the coating while the other part of the pulse is reflected to the detector. At every subsequent interface where a change in refractive index occurs, further parts of the pulse are reflected back and can be detected as additional reflection pulses (FIG. 2). Using the time-delay between the reflection pulses, the coating thickness of the material can be calculated. Detailed information about the measurement are dislosed in Zeitler et al., Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting—a review. Journal of Pharmacy and Pharmacology 59, 209-223 (2007). Ho et al., Analysis of sustained-release tablet film coats using terahertz pulsed imaging, Journal of Controlled Release 119, 253-261 (2007) discloses a good agreement between coating thickness measurements obtained by TPI and microscopic reference data.
Ho et al., Monitoring the film coating unit operation and predicting drug dissolution using terahertz pulsed imaging, Journal of Pharmaceutical Sciences 98, 4866-4876 (2009) discloses the use of TPI technique to monitor the growth of the coating layer with process time during a coating run in off-line measurements.
May et al., Terahertz in-line sensor for direct coating thickness measurement of individual tablets during film coating in real-time, Journal of Pharmaceutical Sciences 100, 1535-1544 (2011) discloses the use of this technology to measure the coating thickness of individual tablets during a coating run (in-line). There are however no reports on the applicability of TPI measurements for thick coating layers (>200 μm) or active coating processes yet.
Both, NIR and Raman spectroscopy are known as a process analytical technology (PAT) tool for a variety of applications such as end point determination in blending, process control of granulation, drying and coating operations. De Beer et al., Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes, Int. J. Pharm. 417, 32-47 (2011) summarizes the state of the art in that respect.
NIR spectroscopy is being discussed as a powerful process analytical technology tool for more than a decade. Gendre et al., Development of a process analytical technology (PAT) for in-line monitoring of film thickness and mass of coating materials during a pan coating operation, Eur. J. Pharm. Sci. 43, 244-250 (2011) and Gendre et al., Real-time predictions of drug release and end point detection of a coating operation by in-line near infrared measurements, Int. J. Pharm. 421, 237-43 (2011) disclose the use of NIR spectroscopy to in-line monitor the film thickness and the corresponding effect on in vitro-release of modified release coatings. Active coatings are however not disclosed. Kim et al., Investigation of an active film coating to prepare new fixed-dose combination tablets for treatment of diabetes describe active film coatings containing glimepiride and the use of off-line NIR spectroscopy to monitor the coating process. Content uniformity data are however not reported while reported single values range from 93.1 to 108.1%. Accordingly, FIGS. 6 and 7 of Kim et al. also display significant variability.
The use of Raman spectroscopy as a potential process analytical technology tool has been proposed more recently. In comparison to NIR spectroscopy, Raman spectroscopy offers higher structural selectivity. Müller et al., Prediction of dissolution time and coating thickness of sustained release formulations using Raman spectroscopy and terahertz pulsed imaging, Eur J Pharm Biopharm. 80, 690-697 (2012) disclose the use of Raman spectroscopy to in-line monitor the film thickness and the corresponding effect on in vitro-release of modified release coatings. Müller et al., Feasibility of Raman spectroscopy as PAT tool in active coating. Drug. Dev. Ind. Pharm. 36, 234-243 (2010) and Müller et al., Validation of Raman spectroscopic procedures in agreement with ICH guideline Q2 with considering the transfer to real time monitoring of an active coating process, J. Pharm. Biomed. Anal. 53, 884-894 (2010) disclose the use of Raman spectroscopy to determine the amount of coatings containing the active pharmaceutical ingredient diprophylline. The active coatings were applied to uniform cores in these studies. Active coatings on bilayer tablets are however not disclosed. Obviously, bilayer tablet cores provide an inhomogeneous background for any spectroscopic measurements.
Thus, there is a need to provide a reliable method for endpoint control of the active coating step, especially onto bilayer tablet cores.
Thus, there is a need to provide a reliable method for endpoint control of the active coating step, especially onto bilayer tablet cores comprising Nifedipine.
Thus, there is a need to provide a reliable method for endpoint control of the active coating step for candesartan cilexetil, especially onto bilayer tablet cores comprising Nifedipine.
Thus, there is a need to provide a reliable method for endpoint control of the active coating step for candesartan cilexetil, especially onto osmotic release bilayer tablet cores comprising Nifedipine.